The leading cause of dementia is Alzheimer's disease (AD), which is characterized by a progressive loss of cognitive function and memory, ultimately leading in death. It is estimated that over 5 million Americans currently suffer for AD, and the direct healthcare cost associated with AD and related dementias annually exceeds $145 billion. As the population ages over the next several decades, the health-care burden presented by AD will be staggering. Understanding the pathogenesis of this age-related disease is c critical to the development of effective therapies and is the primary motivation for this research proposal. Deposition of the Amyloidal (3 (A|3) peptide in the extracellular space of the brain constitutes one of the key pathological hallmarks of AD. Inheritance of apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset AD identified so far, while apoE2 inheritance appears to be protective. Toxic accumulation of the A(3 peptide is likely regulated by the rates of its production and its clearance from the interstitial fluid (ISF) of the brain;since apoE does not affect the synthesis of Ap, it likely regulates A|3 clearance from the ISF. Our group and others have shown that the binding between apoE and Ap influences Ap deposition and its clearance ifrom the brain. Abundant evidence indicates that the low density lipoprotein receptor (LDLR) is a major apoE receptor in the brain, likely providing an important clearance route for soluble Ap from the ISF. The process by which LDLR regulates Ap clearance in the context of human apoE isoforms remains poorly understood. My objective is to determine the role of LDLR in regulating human apoE-mediated clearance of Ap from the ISF. I hypothesize that apoE-mediated elimination of Ap from the ISF is facilitated by LDLR and follows a pattern that is isoform-dependent such that Ap clearance rate for apoE2 >apoE3 >apoE4. In Specific Aim 1,1 will use our in vivo microdialysis technique to directly assess Ap clearance in mice expressing each of the human apoE isoforms, comparing them to the same mice lacking LDLR. To complement this study, I will determine the AP half-life in the ISF of mice overexpressing LDLR and each of the human apoE isoforms. In Specific Aim 2,1 will analyze extracellular pools of Ap in mice overexpressing LDLR and each of the human apoE isoforms at ages prior to and after Ap deposition to assess LDLR's regulation of Ap levels in regions of the brain where deposits form. To assess the effect of LDLR on Ap deposition in the context of human apoE, I will quantify plaque load in brain sections from each of the groups of mice. The relevance of my proposed research plan to public health is that understanding the mechanisms by which LDLR and human apoE act to mediate Ap clearance will be critical to designing effective new therapies for AD.